title: NF-κB1 inhibits NOD2-induced cytokine secretion through ATF3-dependent mechanisms.
abstract: Regulation of microbially induced cytokine secretion is critical in intestinal immune homeostasis. NOD2, the Crohn's disease-associated bacterial peptidoglycan sensor, activates the NF-κB pathway. After chronic NOD2 stimulation in human macrophages, cytokine secretion is significantly attenuated, similar to the situation in the intestinal environment. We find that NF-κB1 (p105/p50) expression is upregulated with chronic NOD2 stimulation and is required for attenuation of cytokine secretion in vitro in human macrophages and in vivo in mice. Upon chronic NOD2 stimulation, regulation of both activating (H3K4Me2 and H4Ac) and inhibitory (H3K27Me3) histone modifications was observed within cytokine gene promoters; these outcomes were NF-κB1 dependent. In addition to enhanced binding to cytokine gene promoters with chronic NOD2 stimulation, NF-κB1 bound to the promoter of the transcriptional repressor, ATF3. ATF3 was then induced and bound to cytokine gene promoters; both features were impaired upon NF-κB1 knockdown. Restoring ATF3 expression under NF-κB1 knockdown conditions restored NOD2-mediated cytokine downregulation. Finally, NF-κB1 and ATF3 cooperate with other inhibitory pathways, including IRAKM and secreted mediators, to downregulate cytokine secretion after chronic NOD2 stimulation. Therefore, we identify NF-κB1 and ATF3 as critical mechanisms through which NOD2 downregulates cytokines and contributes to intestinal immune homeostasis.
authors.affiliation: Department of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zheng
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000276:immunology; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D016207:Cytokines; D006657:Histones; D052002:NF-kappa B p50 Subunit; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C073701:Nfkb1 protein, mouse